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p38-MAPK inhibition and endotoxin induced tubular dysfunction in menIntensive and Respiratory Care Unit, Department of Internal Medicine, University Hospital Groningen, Groningen, The Netherlands
Intensive and Respiratory Care Unit, Department of Internal Medicine, University Hospital Groningen, Groningen, The Netherlands, j.e.tulleken{at}int.azg.nl
Intensive and Respiratory Care Unit, Department of Internal Medicine, University Hospital Groningen, Groningen, The Netherlands
R. W. Johnson Pharmaceutical Research Institute, Bassersdorf, Switzerland
Intensive and Respiratory Care Unit, Department of Internal Medicine, University Hospital Groningen, Groningen, The Netherlands Background: To evaluate the possibility of preventing endotoxin induced renal damage by p38-MAPK inhibition in a human model. Design and Methods: Twenty-one healthy young male volunteers received 4 ng/kg Escherichia coli endotoxin as a single dose. Four groups of volunteers received an oral dose of placebo or 350, 700 or 1400 mg RWJ-67657, a p38-MAPK inhibitor, 20 min before endotoxin infusion. Urine samples were collected at set time intervals. The urinary excretion rate of ß2-microglobulin and N-acetyl-ß-D-glucosaminidase, as indicators of tubular dysfunction was determined. Results: There was a significant increase of ß2-microglobulin and N-acetyl-ß-D-glucosaminidase urine excretion rate after endotoxin infusion in the placebo group. p38-MAPK inhibition prevented the increase of markers for tubulopathy.
Conclusions: Endotoxin infusion induces measurable tubular damage. Blocking the p38-MAPK may prevent this damage. The mechanism is unclear, but blocking TNF-
Key Words: Endotoxin renal failure p38-MAPK inhibition tubulopathy
Journal of Endotoxin Research, Vol. 10, No. 6,
402-405 (2004) |
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release is a possible explanation.